1:1 conversion ratio when transitioning from IR hydrocodone8

This table cannot be used to convert from Zohydro® ER with BeadTek™ to IR hydrocodone.

For breakthrough pain, patients may require a dose increase of Zohydro® ER with BeadTek™ or a rescue medication with an appropriate dose of an IR analgesic.8

Discontinue all other around-the-clock opioid drugs when Zohydro® ER with BeadTek™ therapy is initiated. Instruct patients to never take a dose of Zohydro® ER with BeadTek™ beyond what is prescribed. Zohydro® ER with BeadTek™ is NOT indicated as an as-needed (prn) analgesic.8

Conversion to Zohydro® ER with BeadTek™ (not equianalgesic doses)8

ER OPIOID CONVERSION CALCULATOR

Select Opioid

Enter Total Daily Oral Dose

Enter Total Daily Oral Dose

mg

=

Approximate Twice-Daily 12-Hour Zohydro® ER with BeadTek™ Dose 0 mg

It is extremely important to monitor all patients closely
when converting from methadone to other opioid
agonists. The ratio between methadone and other
opioid agonists may vary widely as a function of
previous dose exposure. Methadone has a long half-life
and tends to accumulate in the plasma.

Zohydro® ER 50 mg capsules, a single dose of Zohydro® ER greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

FOR DEMONSTRATION PURPOSES ONLY. Do not rely solely on calculator when converting patients from other opioid treatments. For more information about dosages and conversion, read the full Prescribing Information. The guidance provided above is a reasonable example of proper dose conversion to Zohydro® ER. It is not a replacement for clinical decision making, which should be modified and tailored to individual patient response. These conversion factors have not been verified in well-controlled, multiple-dose trials. Because hydrocodone and other opioid analgesics can affect patients very differently, it is safer to underestimate a patient’s 24-hour dose and provide rescue medication as needed than to overestimate the 24-hour dose.

START FAST, FINISH STRONG

Starting Zohydro® ER with BeadTek™

Zohydro® ER with BeadTek™ is taken once every 12 hours8

Discontinue all other around-the-clock opioid drugs when Zohydro® ER with BeadTek™ therapy is initiated.

Instruct patients to only take Zohydro® ER with BeadTek™ exactly as prescribed.

Initiate the dosing regimen for each patient individually, accounting for prior analgesic treatment experience and risk factors for addiction, abuse, or misuse.

Discontinue all other around-the-clock opioid drugs when Zohydro® ER with BeadTek™ therapy is initiated.

Instruct patients to only take Zohydro® ER with BeadTek™ exactly as prescribed.

Initiate the dosing regimen for each patient individually, accounting for prior analgesic treatment experience and risk factors for addiction, abuse, or misuse.

Instruct patients to swallow capsules whole, one at a time, and with enough water to ensure complete swallowing immediately after placing in mouth. Zohydro® ER with BeadTek™ can be taken with or without food.

Titration8

Zohydro® ER with BeadTek™ is taken once every 12 hours

Titrate Zohydro® ER with BeadTek™ to a dose that provides adequate pain management and minimizes adverse events, preferably by increments of 10 mg every 12 hours every 3 to 7 days

ZOHYDRO ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ZOHYDRO ER and monitor all patients regularly for the development of these behaviors and conditions.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of ZOHYDRO ER. Monitor for respiratory depression, especially during initiation of ZOHYDRO ER or following a dose increase. Instruct patients to swallow ZOHYDRO ER capsules whole; crushing, chewing, or dissolving ZOHYDRO ER capsules can cause rapid release and absorption of a potentially fatal dose of hydrocodone.

Accidental Ingestion

Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in a fatal overdose of hydrocodone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Cytochrome P450 3A4 Interaction

The concomitant use of ZOHYDRO ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving ZOHYDRO ER and any CYP3A4 inhibitor or inducer.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of ZOHYDRO ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking ZOHYDRO ER. The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

INDICATIONS AND USAGE

ZOHYDRO® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

LIMITATIONS OF USE

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve ZOHYDRO ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

ZOHYDRO ER is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS

Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Hypersensitivity to hydrocodone or to any other components of ZOHYDRO ER.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse

ZOHYDRO ER contains hydrocodone, a Schedule II controlled substance. As an opioid, ZOHYDRO ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as ZOHYDRO ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ZOHYDRO ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing ZOHYDRO ER, and monitor all patients receiving ZOHYDRO ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of ZOHYDRO ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ZOHYDRO ER, but use in such patients necessitates intensive counseling about the risks and proper use of ZOHYDRO ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of ZOHYDRO ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ZOHYDRO ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ZOHYDRO ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ZOHYDRO ER.

To reduce the risk of respiratory depression, proper dosing and titration of ZOHYDRO ER are essential. Overestimating the ZOHYDRO ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ZOHYDRO ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and mange accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of ZOHYDRO ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ZOHYDRO ER-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using ZOHYDRO ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ZOHYDRO ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved.

Concomitant use of ZOHYDRO ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using ZOHYDRO ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ZOHYDRO ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum duration of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when ZOHYDRO ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on ZOHYDRO ER therapy. The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of ZOHYDRO ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: ZOHYDRO ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ZOHYDRO ER.

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particular when initiating and titrating ZOHYDRO ER and when ZOHYDRO ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

ZOHYDRO ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of ZOHYDRO ER. In patients with circulatory shock, ZOHYDRO ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ZOHYDRO ER in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ZOHYDRO ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ZOHYDRO ER.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ZOHYDRO ER in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

ZOHYDRO ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Hydrocodone in ZOHYDRO ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening of symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in ZOHYDRO ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ZOHYDRO ER therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ZOHYDRO ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Risks of Driving and Operating Machinery

ZOHYDRO ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ZOHYDRO ER and know how they will react to the medication.

Addiction, Abuse, and Misuse
ZOHYDRO ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing ZOHYDRO ER and monitor all patients regularly for the development of these behaviors or conditions.

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of ZOHYDRO ER. Monitor for respiratory depression, especially during initiation of ZOHYDRO ER or following a dose increase. Instruct patients to swallow ZOHYDRO ER capsules whole; crushing, chewing, or dissolving ZOHYDRO ER capsules can cause rapid release and absorption of a potentially fatal dose of hydrocodone.

Accidental Ingestion Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in a fatal overdose of hydrocodone.

Neonatal Opioid Withdrawal SyndromeProlonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Cytochrome P450 3A4 Interaction The concomitant use of ZOHYDRO ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving ZOHYDRO ER and any CYP3A4 inhibitor or inducer.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of ZOHYDRO ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking ZOHYDRO ER. The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

INDICATIONS AND USAGE

ZOHYDRO® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

LIMITATIONS OF USE

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve ZOHYDRO ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

ZOHYDRO ER is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS

Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Hypersensitivity to hydrocodone or to any other components of ZOHYDRO ER.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse

ZOHYDRO ER contains hydrocodone, a Schedule II controlled substance. As an opioid, ZOHYDRO ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as ZOHYDRO ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ZOHYDRO ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing ZOHYDRO ER, and monitor all patients receiving ZOHYDRO ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of ZOHYDRO ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ZOHYDRO ER, but use in such patients necessitates intensive counseling about the risks and proper use of ZOHYDRO ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of ZOHYDRO ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ZOHYDRO ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ZOHYDRO ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ZOHYDRO ER.

To reduce the risk of respiratory depression, proper dosing and titration of ZOHYDRO ER are essential. Overestimating the ZOHYDRO ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ZOHYDRO ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and mange accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of ZOHYDRO ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ZOHYDRO ER-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using ZOHYDRO ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ZOHYDRO ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved.

Concomitant use of ZOHYDRO ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using ZOHYDRO ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ZOHYDRO ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum duration of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when ZOHYDRO ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on ZOHYDRO ER therapy. The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of ZOHYDRO ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: ZOHYDRO ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ZOHYDRO ER.

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particular when initiating and titrating ZOHYDRO ER and when ZOHYDRO ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

ZOHYDRO ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of ZOHYDRO ER. In patients with circulatory shock, ZOHYDRO ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ZOHYDRO ER in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ZOHYDRO ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ZOHYDRO ER.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ZOHYDRO ER in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

ZOHYDRO ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Hydrocodone in ZOHYDRO ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening of symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in ZOHYDRO ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ZOHYDRO ER therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ZOHYDRO ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Risks of Driving and Operating Machinery

ZOHYDRO ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ZOHYDRO ER and know how they will react to the medication.